1. Field of the Invention
The present invention relates to medical systems and, more specifically, to a system for estimating insulin sensitivity.
2. Description of the Related Art
Diabetes is a chronic disease characterized by the inefficiency of the pancreas to produce insulin (type-1 diabetes, T1DM), or by malfunctions in both insulin secretion and action (type-2 diabetes, T2DM). As a result, in a diabetic subject the plasma glycaemic level exceeds the normal range, with several long and short term complications. Diabetes is taking on epidemic proportions with over 220 million individuals affected by this disease, a number which is expected to grow to 366 million by the year 2030. The rapid, constant increase of diabetic patients makes this disease one of the social-health emergencies of the third millennium. Most diabetics follow a metabolic monitoring therapy based on a combination of insulin injections and/or drugs, diet and physical exercise. The therapy is determined by the physician on the basis of glycaemia level measurements that the patient measures by him or herself in capillary blood 3 or 4 times a day (self-monitoring). This approach presents inevitable shortcomings due to the low amount of glycaemia data available related to the high glycaemia range during the day. Due to the shortcomings of the monitoring system, glycaemia may exceed normal limits (between 70 and 180 mg/dL). Hyperglycaemia, a situation in which the concentration of glucose in blood is higher than 180 mg/dL, causes various long-term complications such as cardiovascular disease, hypertension, retinopathies, etc.; while on the short-term, hypoglycaemia, glucose concentration lower than 70 mg/dL, may even be more dangerous, e.g. it may lead to diabetic coma, also because it may be difficult for the patient to recognize, particularly at night.
Extensive studies, including the Diabetes Control and Complications Trial (DCCT), have repeatedly demonstrated that the most effective way to prevent long-term complications of T1DM and T2DM is by maintaining BG levels within a normal range using intensive therapy. However, the same studies have also documented adverse effects of intensive therapy, the most acute of which is the increased risk of hypoglycemia which can brings also to coma and death. On one hand, intensive therapy could lead to improve metabolic control and reduce complications in T1DM and T2DM; on the other, intensive therapy was associated with an increase in hypoglycemia events. Thus, people with diabetes face the long-life optimization problem of maintaining strict metabolic control without increasing their risk of hypoglycemia.
The standard therapy, especially for T1DM, is based on multiple daily injection of insulin (bolus and basal doses), diet and physical exercise, tuned according to self-monitoring of blood glucose (SMBG) levels 3-4 times a day. However, in the last 10 years, new possibilities in diabetes therapy have been opened thanks to the availability of continuous glucose monitoring (CGM) sensors and insulin delivery systems, which substitute self-monitoring blood glucose (SMBG) and multiple daily injection therapy (MDI), respectively.
New noninvasive or minimally-invasive CGM devices can compensate the lack of information of the traditional 3-4 self-monitoring blood glucose (SMBG) measurements: in fact, they can measure, in real-time, the glycaemia level at continuous time (from every 1 to 5 minutes, according to the sensor) for up to several days (from 3 to 7 days, according to the technology), allowing the improvement of diabetes management. The most widespread insulin delivery systems are subcutaneous, but in a lesser extent also the intraperitoneal way is used even if nowadays it's a complex technology to be applied in everyday life, which, differently from multiple daily injection therapy, allows one to generally intensify insulin therapy with a reduced intrinsically associated high rate of hypoglycemia, improving diabetes management. Conventional insulin pumps can deliver insulin to the patient and can be configured to deliver rapid-acting insulin 24 hours a day: the total daily dose of insulin (TDI) can be divided into basal rates, continuously delivered over 24 hours keeping the blood glucose concentration levels in normal desirable range between meals as well as overnight which can be pre-programmed or manually changed according to various daily activities of the patient; and bolus doses, delivered before meals, to counteract carbohydrate's loads, or during episodes of high blood glucose concentration levels to bring glycaemia to normal desirable range.
In order to correctly evaluate the amount of insulin which should be present in the administered bolus, it would be fundamental to know the value of insulin sensitivity (SI), which corresponds to the ability of insulin to stimulate glucose utilization and inhibit glucose production. In fact, the knowledge of patient specific SI and its daily variation will help in determining optimal insulin treatment. Several indexes have been published, but the two most important have been favored in the past 3 decades: the clamp insulin sensitivity, SIDF, defined by DeFronzo as the ratio of glucose injection and insulin concentration during the hyperinsulinemic euglycemic clamp and the insulin sensitivity, SIBC, defined by Bergman and Cobelli which uses minimal model of glucose regulation during an intravenous glucose tolerance test (IVGTT).
Recently, several methods for determining insulin sensitivity from oral glucose tolerance test (OGTT) or meal test (MTT) have been proposed, but the difficulty with oral tests is that the input of the system (rate of glucose appearance) is unknown. An approach to simultaneously identifying parameters describing glucose absorption and insulin sensitivity using seven or more blood samples from MTT or OGTT has been developed by Dalla Man et al. and was validated against multiple tracer methods in non-diabetic subjects and results were well correlated with results from hyperinsulinemic clamps. However, this method requires at least seven blood samples to measure plasma glucose and insulin concentrations and the identification of a model with a sophisticated modeling software. Caumo et al. derived an index of insulin sensitivity with an integral approach, but it also requires frequent measurements of plasma glucose and insulin concentration after the meal; moreover, the method requires that both glucose and insulin concentrations have returned to basal values at the end of the experiment. This is a big limitation, since, in type 1 diabetic subjects, it is not unusual that glucose does not return to pretest glycemic basal value due to errors in insulin administration.
Other more empiric methods for determining insulin sensitivity from OGTT have also been proposed. Stumvoll et al. empirically obtained an insulin sensitivity index based on glucose and insulin measurements during an OGTT that was correlated with the glucose infusion rate during a hyperinsulinemic clamp. Matsuda et al. developed a composite insulin sensitivity index based on both fasting and mean values of glucose and insulin and showed that this measure was correlated with results from an hyperinsulinemic clamp. Hansen et al. empirically determined measures of insulin sensitivity from OGTT that were correlated with SI measured by IVGTT. However, all of them use plasma measurements. A new empiric approach to evaluate insulin sensitivity has been proposed by Breton and Kovatchev. It employs routine self-monitoring blood glucose (SMBG) data, collected over a period of 2-6 weeks and it is based on the theory of risk analysis of blood glucose data, combined with basic patient measurements. This method has the advantage to be easy to implement and uses simple data collected in normal daily life conditions, but, due to the long-time collected data, this not takes into account the intraday variability of this index which can be present in person's natural environment.
Therefore, there is a need for a method to estimate insulin sensitivity by using new technologies such as continuous glucose monitoring and subcutaneous insulin infusion devices which provide much more information about patient conditions respect to other devices. The goal of this invention is to use these new minimally-invasive technologies to estimate this fundamental parameter to optimize the control therapy in type 1 diabetes.